JAK1 pathway inhibitors for use in the treatment of chronic lung allograft dysfunction

Abstract

The present invention relates primarily to JAK1 pathway inhibitors for use in the treatment of chronic lung allograft dysfunction, in particular to JAK1 pathway inhibitors and their use in the treatment of chronic lung allograft dysfunction, such as for example bronchiolitis obliterans syndrome.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202080024215.0, filed on March 5, 2020, entitled "JAK1 pathway inhibitor for treating chronic lung allogeneic graft dysfunction". Technical Field

[0002] This disclosure relates to JAK1 pathway inhibitors and their use in the treatment of chronic lung allogeneic graft dysfunction, such as bronchiolitis obliterans syndrome. Background Technology

[0003] Allogeneic lung transplantation is an effective treatment for various end-stage lung diseases, including COPD, ILD, and cystic fibrosis. In 2016, over 4,000 lung transplants were performed globally, with approximately 2,300 in the United States (2018 OPTN / SRTR Registry). Although 1-year and 3-year survival rates have improved, long-term survival remains stagnant, with a median overall survival of 6.1 years (Chambers, D. et al., JHLT, 2017, Vol. 36, No. 10). The most common cause of death after lung transplantation within one year is chronic lung graft dysfunction (CLAD); the most common subtype of CLAD is bronchiolitis obliterans syndrome (BOS). BOS following lung transplantation affects approximately 50% of patients who survive more than 5 years and is the leading cause of death in patients who survive more than 1 year after transplantation (Chambers, D. et al., JHLT, 2017, Vol. 36, No. 10). BOS following lung transplantation is characterized by allogeneic reactive immune infiltration, ultimately leading to progressive bronchiectasis, fibrosis, and eventual organ failure (Boehler, A. et al., Eur. Respir. J., Vol. 22, No. 6, 1007-1018, 2003). Despite prophylactic treatment with immunosuppressants, the incidence of BOS following lung transplantation remains unchanged. Treatment trials for BOS following lung transplantation are few, and currently, the FDA has not approved any agents for the prevention or treatment of BOS following lung transplantation. Interventions investigated in the treatment of BOS after lung transplantation include azithromycin, altered immunosuppressive regimens, everolimus, montelukast, nebulized cyclosporine, nebulized aerosolized tacrolimus, aerosolized alemtuzumab, whole lymphatic irradiation, photopheresis, and eventual retransplantation. Of these, for eligible patients, lung retransplantation is the only definitive treatment for progressive BOS. Survival rates after a second transplant are significantly lower at 2.6 years than after the first transplant (Thomas, M. et al., Ann. Thorac. Surg. 2015; 100:452–7).

[0004] Therefore, there is a need to develop new therapies for the prevention and treatment of chronic lung allogeneic graft dysfunction, such as bronchiolitis obliterans syndrome. This application addresses this need, as well as other needs. Summary of the Invention

[0005] This article provides a method for treating chronic lung allogeneic graft dysfunction (e.g., bronchiolitis obliterans syndrome) in subjects of need, comprising administering to the subject a therapeutically effective amount of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0006] This article provides a JAK1 pathway inhibitor for the treatment of chronic lung allogeneic graft dysfunction (e.g., bronchiolitis obliterans syndrome) in subjects of need.

[0007] This article provides the use of JAK1 pathway inhibitors in the manufacture of medicines for treating patients with chronic lung allogeneic graft dysfunction (e.g., bronchiolitis obliterans syndrome). Detailed Implementation

[0008] The present invention particularly provides a method for treating chronic lung allogeneic graft dysfunction, such as bronchiolitis obliterans syndrome, in a subject in need, comprising administering to the subject a therapeutically effective amount of a JAK1 pathway inhibitor (e.g., a JAK1 / 2 inhibitor or a JAK1 inhibitor) or a pharmaceutically acceptable salt thereof.

[0009] Diagnosis of post-lung transplant-associated lung disease (BOS) can be made clinically and is defined by a persistent decline in lung function as measured by FEV1. Other causes of post-transplant decline for diagnosis of BOS include acute rejection, infection, native lung problems in single-lung recipients, excessive recipient weight gain, anastomotic dysfunction, respiratory muscle dysfunction, effusion, or technical problems (such as erroneous measurements due to equipment malfunction), as well as other causes that can be ruled out as lung graft dysfunction (Meyer, KC, et al. Eur. Respir. J. 2014; 44: 1479–1503).

[0010] The BOS classification scheme (the recognized BOS grading system after lung transplantation) is based on vital capacity assessment of a sustained decline in FEV1 to ≤ 80% of the post-transplant baseline FEV1. The baseline can be defined as the two best FEV1 values ​​(or FEV1 values) separated by ≥ 3 weeks after functional recovery and stabilization following lung transplantation. 25-75%The average value. The latest update provided below includes a new category, 0p grade, added to ensure early diagnosis of BOS after lung transplantation. (Meyer, KC, et al. Eur. Respir. J. 2014; 44: 1479–1503). Table 1 is adapted from Meyer, KC, et al. Eur. Respir. J. 2014; 44:1479–1503, which is incorporated herein by reference in its entirety. FEV1: Forced expiratory volume in 1 second; FEF 25-75% Forced expiratory flow rate at 25-75% of forced vital capacity.

[0011] Table 1. BOS Classification Scheme

[0012]

[0013] There is no standard care or consensus treatment algorithm for BOS treatment, and few high-quality randomized trials have demonstrated a significant benefit for BOS patients (Meyer, KC, et al. Eur. Respir. J. 2014; 44: 1479–1503).

[0014] The methods described in this article utilize JAK1 pathway inhibitors, particularly selective JAK1 / 2 and JAK1 inhibitors. JAK1 plays a central role in many cytokine and growth factor signaling pathways, and dysregulation of these pathways can lead to or contribute to disease states. JAK1 has been shown to work in conjunction with other JAKs to mediate the signaling of many inflammatory cytokines associated with many inflammatory conditions.

[0015] Itacitinib (a selective JAK1 pathway inhibitor) is currently undergoing clinical trials for the treatment of acute and chronic post-HSCT GVHD. Chronic GVHD can affect any organ in the body, most commonly the skin, liver, and intestines. Chronic GVHD can also affect the lungs, with clinical presentations nearly identical to post-lung transplant BOS. The association between pulmonary cGVHD and post-lung transplant BOS was first described in 1995, a study that collected clinical and histological data from nine patients with pulmonary cGVHD and post-lung transplant BOS. Both groups had similar signs and symptoms, including progressive dyspnea and an irreversible obstructive pattern, as well as similar outcomes and histology, including diffuse inflammation leading to bronchiectasis (Philit et al., Eur. Respir. J. 1995, 8:551-558).

[0016] Lung cGVHD is triggered during transplantation through the development of normal tissue damage, leading to a tissue injury response characterized by the release of cytokines, Toll-like receptor agonists, neutrophils, platelets, and vasculitis (Cooke et al., Biol. Blood Marrow Transplant 2017, 23:211-234). CD4 and CD8 cells, as well as Th17 cells, are recruited to the site; however, due to thymic injury or dysfunction, negative selection of these cells is impaired, and autologous reactive T cell clones persist. Furthermore, the necessary immunosuppressive regimens used in cGVHD, including CNI, result in T cell reactivity. reg Ultimately, the initial T-cell response leads to the activation of various innate and adaptive immune cells, including T cells, B cells, and NK cells, as well as APCs to the site, resulting in the upregulation of pro-inflammatory cytokines TGFβ, PDGFα, TNFα, and IL17. This chronic inflammation and fibroblast recruitment leads to collagen deposition and persistent dysfunction in target organs, fibrosis, and eventual resolution (Cooke et al., Biol. Blood Marrow Transplant 2017, 23:211-234).

[0017] Many of the same biological principles are inherent in post-lung transplant BOS. The key difference is that in cGVHD, the immune response is abnormal, leading to transplanted stem cells attacking host tissues, while in lung transplant BOS, the immune response is physiologically normal, yet still results in poor patient outcomes. In post-lung transplant BOS, the precipitating event of the allogeneic reactive acute inflammatory phase is well-defined—the implantation of the allogeneic lung transplant; however, it should be noted that, similar to cGVHD, patients experiencing graft tissue damage events leading to acute rejection, CMV infection, and other tissue damage phenomena such as GERD and cold ischemia time are more likely to develop post-lung transplant BOS (Meyer, KC, et al. Eur. Respir. J. 2014; 44: 1479–1503). Thymic dysfunction seen in cGVHD is not associated with post-lung transplant BOS because allogeneic reactive T cells are not negatively selected. However, importantly, the roles of early CD4, CD8, and Th17 cell infiltration, and subsequent recruitment of B cells, NK cells, and APCs, are well documented in post-lung transplantation BOS, even when these are physiologically appropriate (Boehler and Estenne, Eur. Respir. J. 2003, 22:1007-1018; Gupta et al., Am. J. Respir. Cell Mol. Biol. 2017, 56:708-715; Fukami et al., Am. J. Transplant, 2012, 12:867-876; Hodge et al., J. Heart Lung Transplant, 2012, 31:888-895; Leonard et al., Am. J. Respir. Crit. Care Med. 2000, 161:1349-1354). Similar to cGVHD, maintenance immunosuppressive regimens using CNIs induce T... reg Depletion and inhibition (Meyer, KC, et al. Eur. Respir. J. 2014; 44:1479–1503). Finally, every known cytokine (including TGFβ, PDGFα, TNFα, and IL-17) and cellular mediators of abnormal tissue repair were documented in post-lung transplantation BOS.

[0018] Furthermore, in mouse models, prophylactic and therapeutic administration of itatinib at doses of 60 mg / kg / day or 120 mg / kg / day has been demonstrated to improve GVHD scores, thus indicating clinical efficacy in allogeneic mouse models. The JAK inhibitors ruxolitinib (a JAK1 / 2 inhibitor) and itatinib have shown clinical efficacy in acute GVHD (aGVHD); in addition, ruxolitinib has demonstrated clinical efficacy in chronic GVHD (cGVHD).

[0019] Notably, in a pulmonary cGVHD study, 4 out of 5 patients had an FEV1 response, defined as an increase in FEV1 ≥ 10%. Furthermore, a study examining ruxolitinib use in 5 pediatric patients with pulmonary cGVHD (4 evaluable) showed two responses, with one patient experiencing a 9% increase in FEV1. Four out of five patients were able to completely discontinue steroids, and ultimately, patients were able to reduce their steroid requirements by > 50% (Schoettler et al., Bone Marrow Transplantation, 2019, 54:1158-1160). In addition to ruxolitinib, itatinib has shown significant clinical activity in patients with aGVHD. A recent study evaluated the safety and efficacy of two doses of itatinib (200 mg QD and 300 mg QD) in treatment-naïve or steroid-refractory aGVHD patients.

[0020] Therefore, this article provides a method for treating chronic lung allogeneic graft dysfunction in a subject, the method comprising administering to the subject a JAK1 pathway inhibitor (e.g., a JAK1 / 2 inhibitor or a selective JAK1 inhibitor) or a pharmaceutically acceptable salt thereof.

[0021] In some implementations, chronic lung allogeneic graft dysfunction is defined as bronchiolitis obliterans syndrome.

[0022] In some implementations, the subject is a lung transplant recipient (e.g., a single lung transplant recipient or a double lung transplant recipient).

[0023] In some implementation schemes, the subjects are recipients of double lung transplants.

[0024] In some implementations, the subjects had grade 0, 0p, 1, 2 or 3 obliterative bronchiolitis syndrome as defined by the International Society for Heart and Lung Transplantation (ISHLT) criteria.

[0025] In some implementations, the subjects had grade 0p, 1, 2 or 3 obliterative bronchiolitis syndrome as defined by the International Society for Heart and Lung Transplantation (ISHLT) criteria.

[0026] In some implementation schemes, the subjects had grade 1 or 2 obliterative bronchiolitis syndrome as defined by the International Society for Heart and Lung Transplantation (ISHLT) criteria.

[0027] In some implementations, the subject's FEV1 score decreases to less than or approximately 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of the post-transplant baseline FEV1. These values ​​can be used to define a range, such as from approximately 50% to approximately 75%.

[0028] In some implementations, the subject's FEF 25-75% The values ​​are greater than, less than, or approximately 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%. These values ​​can be used to define a range, such as from approximately 60% to approximately 80%.

[0029] In some implementations, the subject had grade 0 obliterative bronchiolitis syndrome, where grade 0 obliterative bronchiolitis syndrome was defined as a FEV1 score that decreased to less than 100% but greater than 90% of the post-transplant baseline FEV1, and / or FEV1. 25–75% Greater than 75% of the post-transplant baseline.

[0030] In some implementations, the subject had grade 0p obliterative bronchiolitis syndrome, where grade 0p obliterative bronchiolitis syndrome was defined as a decrease in FEV1 score to 81% to 90% of the baseline FEV1 after transplantation, and / or a baseline FEV1 score of 0. 25–75% Less than or equal to 75% of the post-transplant baseline.

[0031] In some implementations, the subjects had grade 1 obliterative bronchiolitis syndrome, in which grade 1 obliterative bronchiolitis syndrome was defined as a decrease in FEV1 score to 66% to 80% of the post-transplant baseline FEV1.

[0032] In some implementations, the subjects had grade 2 obliterative bronchiolitis syndrome, in which grade 2 obliterative bronchiolitis syndrome was defined as a decrease in FEV1 score to 51% to 65% of the post-transplant baseline FEV1.

[0033] In some implementations, the subjects had grade 3 obliterative bronchiolitis syndrome, where grade 3 obliterative bronchiolitis syndrome was defined as an FEV1 score that decreased to less than or equal to 50% of the post-transplant baseline FEV1.

[0034] In some implementations, treatment of bronchiolitis obliterans syndrome includes an increase in FEV1 of approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% at approximately 4, 8, 12, 3, 4, 5, or 6 months after the first administration of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0035] In some implementations, treatment of bronchiolitis obliterans syndrome includes an increase in FEV1 of approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% at approximately 4, 8, 12, 3, 4, 5, or 6 months after the first administration of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0036] In some implementations, treatment of bronchiolitis obliterans syndrome includes an increase in FEV1 of about or greater than about 10% approximately 12 weeks after the first administration of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0037] In some implementations, treatment of bronchiolitis obliterans syndrome includes an increase of approximately 10% or more in FEV1 twelve weeks after the first administration of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0038] This article also provides a method for reducing the risk of bronchiolitis obliterans syndrome in subjects, the method comprising administering a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof to the subject.

[0039] This article also provides a method for reducing the risk of lung retransplantation in subjects, the method comprising administering a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof to the subject.

[0040] This article also provides a method for improving FEV1 in subjects with bronchiolitis obliterans syndrome, the method comprising administering to the subject an effective amount of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0041] This article also provides a method for improving the quality of life of subjects suffering from bronchiolitis obliterans syndrome, the method comprising administering to the subject an effective amount of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0042] This article also provides a method for reducing mortality, progressive bronchiectasis, organ failure, and decline in lung function in subjects, increasing recovery and stabilization after lung transplantation, reducing hospitalization, reducing healthcare utilization, and / or lowering the risk of re-transplantation, as well as other potential benefits provided herein, the method comprising administering to subjects an effective amount of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0043] In some implementations, the subject meets one or more of the inclusion criteria listed in Example 1 below. In some implementations, the subject meets one, two, three, four, five, or six of the inclusion criteria listed in Example 1 below. In some implementations, the subject meets all of the inclusion criteria listed in Example 1 below.

[0044] In some implementations, the subject meets four, three, two, one, or none of the exclusion criteria listed in Example 1 below. In some implementations, the subject does not meet any of the exclusion criteria listed in Example 1 below.

[0045] In some implementations, subjects meet all inclusion criteria and have no exclusion criteria, as listed in Example 1 below.

[0046] This article also provides a method for reducing the risk of hospitalization in subjects, the method comprising administering an effective amount of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof to the subject, wherein the subject: (a) has been diagnosed with bronchiolitis obliterans syndrome; (b) has undergone a lung transplant within 1 to 5 years prior to administration of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof; and (c) does not have a decrease in FEV1 due to causes other than bronchiolitis obliterans syndrome.

[0047] In some embodiments, this disclosure may relate to a method of treating a subject with non-transplant-related obliterative bronchiolitis syndrome, comprising administering to the subject a therapeutically effective amount of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof, such as a JAK1 / 2 inhibitor or a pharmaceutically acceptable salt thereof, or a JAK1 inhibitor or a pharmaceutically acceptable salt thereof.

[0048] The method described in this article utilizes JAK1 pathway inhibitors, namely JAK1 / 2 inhibitors or selective JAK1 inhibitors (either of which may be in the form of a pharmaceutically acceptable salt).

[0049] I. JAK1 / 2 inhibitors:

[0050] In some implementations, the JAK1 / 2 inhibitor is baricitinib or a pharmaceutically acceptable salt thereof.

[0051] In some embodiments, the JAK1 / 2 inhibitor is ruxotinib or a pharmaceutically acceptable salt thereof (see, for example, U.S. Patent No. 7,598,257, the disclosure of which is incorporated herein by reference in its entirety). In some embodiments, the salt is ruxotinib phosphate (see, for example, U.S. Patent No. 8,722,693, the disclosure of which is incorporated herein by reference in its entirety).

[0052] In some embodiments, the JAK1 / 2 inhibitor is ruxotinib or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen atoms are replaced by deuterium atoms. In some embodiments, the JAK1 / 2 inhibitor is any compound of U.S. Patent 9,249,149 (which is incorporated herein by reference in its entirety) or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK1 / 2 inhibitor is CTP-543 (compound 111) or a pharmaceutically acceptable salt thereof.

[0053] In some implementations, the JAK1 / 2 inhibitor is a compound of formula I:

[0054]

[0055] Or its pharmaceutically acceptable salt, wherein:

[0056] R 1 Selected from H and D;

[0057] Each R 2 Independently selected from H and D, provided that each R is attached to a common carbon. 2 They are the same;

[0058] Each R 3 Independently selected from H and D, provided that each R is attached to a common carbon. 3 They are the same;

[0059] R 4 Selected from H and D;

[0060] Each R 5 Same and selected from H and D; and

[0061] R 6 R 7 and R 8 Each is independently selected from H and D; the condition is that when R 1 When it is H, each R 2 and each R 3 It is H, R 4 It is H, each R 6 R 7 and R 8 If it is H, then each R 5 It is D.

[0062] In some embodiments, the JAK1 / 2 inhibitor is selected from the following compounds 100-130 in the table below (where R... 6 R 7 and R 8Each is a compound of formula I (wherein H) or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK1 and / or JAK2 inhibitors are selected from the following compounds 200-231 in the table below (wherein R...). 6 R 7 and R 8 Each is a compound of formula I (D) or a pharmaceutically acceptable salt thereof.

[0063]

[0064]

[0065]

[0066] In some embodiments, the JAK1 / 2 inhibitor is baricitinib or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen atoms are replaced by deuterium atoms. In some embodiments, the JAK1 and / or JAK2 inhibitor is any compound of U.S. Patent 9,540,367 (which is incorporated herein by reference in its entirety) or a pharmaceutically acceptable salt thereof.

[0067] II. Selective inhibitors of JAK1

[0068] In some implementations, JAK1 pathway inhibitors are more selective for JAK1 than for JAK2, JAK3, and TYK2 (i.e., selective JAK1 inhibitors). Patients with bronchiolitis obliterans syndrome may benefit from selective JAK1 inhibition. Selective inhibitors of JAK1 may be effective while avoiding unnecessary and potentially adverse effects from inhibiting other JAK kinases. Specifically, maintaining JAK2 inhibition after treatment with a selective JAK1 inhibitor (such as compound 1) may reduce the risk of cytopenia in BOS patients following lung transplantation.

[0069] For example, the compounds described herein, or their pharmaceutically acceptable salts, preferentially inhibit JAK1 compared to one or more of JAK2, JAK3, and TYK2. In some embodiments, the compounds preferentially inhibit JAK1 rather than JAK2 (e.g., JAK2 / JAK1 1000). 50 (ratio > 1). In some embodiments, the compound or salt is about 10 times more selective for JAK1 than for JAK2. In some embodiments, such as by measuring IC50 at 1 mM ATP. 50 The calculated selectivity of the compound or salt for JAK1 is about 3 times, about 5 times, about 10 times, about 15 times, or about 20 times higher than that for JAK2 (see, for example, Example A).

[0070] In some embodiments, the JAK1 pathway inhibitor is a compound from Table 2 or a pharmaceutically acceptable salt thereof. The compounds in Table 2 are selective JAK1 inhibitors (i.e., JAK1 pathway inhibitors that are more selective than JAK2, JAK3, and TYK2). IC50 was obtained at 1 mM ATP using the method of Example A. 50 The values ​​are shown in Table 2.

[0071] Table 2

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084] + indicates <10 nM (see Example A for measurement conditions)

[0085] ++ indicates ≤ 100 nM (see Example A for measurement conditions)

[0086] +++ indicates ≤ 300 nM (see Example A for measurement conditions)

[0087] a Data for enantiomer 1

[0088] b Data on enantiomer 2

[0089] In some embodiments, the JAK1 pathway inhibitor is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azacyclobutane-3-yl}acetonitrile or a pharmaceutically acceptable salt thereof.

[0090] In some implementations, the JAK1 pathway inhibitor is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azacyclobutane-3-yl}acetonitrile adipate.

[0091] The synthesis and preparation of {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinyl]piperidin-4-yl}-3[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azacyclobutane-3-yl}acetonitrile can be found, for example, in U.S. Patent Publication No. 2011 / 0224190, filed March 9, 2011; U.S. Patent Publication No. 2013 / 0060026, filed September 6, 2012; and U.S. Patent Publication No. 2014 / 0256941, filed March 5, 2014, each of which is incorporated herein by reference in its entirety.

[0092] In some implementations, the JAK1 pathway inhibitor is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bispyrazol-1-yl)azacyclobutane-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide or a pharmaceutically acceptable salt thereof.

[0093] In some implementations, the JAK1 pathway inhibitor is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bispyrazol-1-yl)azacyclobutane-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide phosphate.

[0094] The synthesis and preparation of 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bispyrazol-1-yl)azacyclobutane-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide and its phosphate can be found, for example, in U.S. Patent Publication No. 2014 / 0343030, filed May 16, 2014, which is incorporated herein by reference in its entirety.

[0095] In some implementations, the JAK1 pathway inhibitor is ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile or a pharmaceutically acceptable salt thereof.

[0096] In some implementations, the JAK1 pathway inhibitor is ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile monohydrate.

[0097] The synthesis of ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thienozo[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile and its characterization in anhydrous and monohydrate forms are described in U.S. Patent Publication No. 2014 / 0121198, filed October 31, 2013, and U.S. Patent Publication No. 2015 / 0344497, filed April 29, 2015, each of which is incorporated herein by reference in its entirety.

[0098] In some embodiments, the compounds in Table 2 are described in U.S. Patent Publication No. 2011 / 0224190, filed March 9, 2011; U.S. Patent Publication No. 2014 / 0343030, filed May 16, 2014; U.S. Patent Publication No. 2014 / 0121198, filed October 31, 2013; U.S. Patent Publication No. 2010 / 0298334, filed May 21, 2010; and U.S. Patent Publication No. 2011 / 0059951, filed August 31, 2010. The synthetic procedures described in U.S. Patent Publication No. 2012 / 0149681, filed November 18, 2011; U.S. Patent Publication No. 2012 / 0149682, filed November 18, 2011; U.S. Patent Publication No. 2013 / 0018034, filed June 19, 2012; U.S. Patent Publication No. 2013 / 0045963, filed August 17, 2012; and U.S. Patent Publication No. 2014 / 0005166, filed May 17, 2013, are used to prepare the materials, each of which is incorporated herein by reference in its entirety.

[0099] In some embodiments, the JAK1 pathway inhibitor is selected from U.S. Patent Publication No. 2011 / 0224190, filed March 9, 2011; U.S. Patent Publication No. 2014 / 0343030, filed May 16, 2014; U.S. Patent Publication No. 2014 / 0121198, filed October 31, 2013; U.S. Patent Publication No. 2010 / 0298334, filed May 21, 2010; U.S. Patent Publication No. 2011 / 0059951, filed August 31, 2010; and others. Compounds thereof, or pharmaceutically acceptable salts thereof, filed on November 18, 2012, U.S. Patent Publication No. 2012 / 0149681, filed on November 18, 2011, U.S. Patent Publication No. 2013 / 0018034, filed on June 19, 2012, U.S. Patent Publication No. 2013 / 0045963, filed on August 17, 2012, and U.S. Patent Publication No. 2014 / 0005166, filed on May 17, 2013, are incorporated herein by reference in their entirety.

[0100] In some implementations, the JAK1 pathway inhibitor is a compound of formula I.

[0101]

[0102] I

[0103] Or its pharmaceutically acceptable salt, wherein:

[0104] X is N or CH;

[0105] L is C(=O) or C(=O)NH;

[0106] A is phenyl, pyridinyl, or pyrimidinyl, each of which is optionally represented by one or two independently selected R groups. 1 Group substitution; and

[0107] Each R 1 It is either fluorine or trifluoromethyl.

[0108] In some embodiments, the compound of formula I is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azacyclobutane-3-yl}acetonitrile or a pharmaceutically acceptable salt thereof.

[0109] In some embodiments, the compound of formula I is 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azacyclobutane-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide or a pharmaceutically acceptable salt thereof.

[0110] In some embodiments, the compound of formula I is [3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)azacyclobutane-3-yl]acetonitrile or a pharmaceutically acceptable salt thereof.

[0111] In some implementations, the JAK1 pathway inhibitor is a compound of formula II.

[0112]

[0113] II

[0114] Or its pharmaceutically acceptable salt, wherein:

[0115] R 2 It is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl or C 3-6 cycloalkyl-C 1-3 Alkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkyl-C 1-3 Each alkyl group is optionally substituted by one, two, or three substituents independently selected from fluorine, -CF3, and methyl;

[0116] R 3 It is H or methyl;

[0117] R 4 It is H, F, or Cl;

[0118] R 5 It is H or F;

[0119] R 6 It is H or F;

[0120] R 7 It is H or F;

[0121] R 8 It is H or methyl;

[0122] R 9 It is H or methyl;

[0123] R10 It is H or methyl; and

[0124] R 11 It is H or methyl.

[0125] In some embodiments, the compound of formula II is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bispyrazol-1-yl)azacyclobutane-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide or a pharmaceutically acceptable salt thereof.

[0126] In some implementations, the JAK1 pathway inhibitor is a compound of formula III.

[0127]

[0128] III,

[0129] Or its pharmaceutically acceptable salt, wherein:

[0130] Cy 4 It is a tetrahydro-2H-pyran ring, which is optionally composed of one or two independently selected from CN, OH, F, Cl, C. 1-3 Alkyl, C 1-3 Halogenated alkyl, cyano-C 1-3 Alkyl, HO-C 1-3 Alkyl, amino, C 1-3 Alkylamino and di(C) 1-3 Substitution of alkyl)amino groups, wherein the C 1-3 Alkyl and di(C) 1-3 The alkyl)amino group is optionally selected independently by one, two, or three elements chosen from F, C1, C2, and C3. 1-3 alkylaminosulfonyl and C 1-3 Alkyl sulfonyl group substituents; and

[0131] R 12 It is CH2-OH, -CH(CH3)-OH or -CH2-NHSO2CH3.

[0132] In some embodiments, the compound of formula III is ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile or a pharmaceutically acceptable salt thereof.

[0133] In some embodiments, the JAK1 pathway inhibitor is an isotopically labeled compound or a pharmaceutically acceptable salt thereof. An "isotopic" or "radiolabeled" compound is a compound of this disclosure in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated into compounds of this disclosure include, but are not limited to, those... 2 H (also written as D for deuterium), 3 H (also written as T for tritium), 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 18 F, 35 S, 36 Cl、 82 Br、 75 Br、 76 Br、 77 Br、 123 I, 124 I, 125 I and 131 I. One or more hydrogen atoms in the compounds disclosed herein may be replaced by deuterium atoms, such as -CD3 replacing -CH3).

[0134] One or more constituent atoms of the compounds described herein may be replaced or substituted with isotopes of atoms of natural or non-natural abundance. In some embodiments, the compound comprises at least one deuterium atom. In some embodiments, the compound comprises two or more deuterium atoms. In some embodiments, the compound comprises 1-2, 1-3, 1-4, 1-5, or 1-6 deuterium atoms. In some embodiments, all hydrogen atoms in the compound may be replaced or substituted with deuterium atoms.

[0135] Synthetic methods that incorporate isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry, Alan F. Thomas (New York, NY, Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange, Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling, James R. Hanson, Royal Society of Chemistry, 2011). Isotope-labeled compounds can be used in a variety of studies, such as NMR spectroscopy, metabolic experiments and / or assays.

[0136] Substitution with a heavier isotope (such as deuterium) may offer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements, and may therefore be preferred in some cases. (See, for example, A. Kerekes et al., J. Med. Chem. 2011, 54, 201-210; R. Xu et al., J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular, substitution at one or more metabolic sites may provide one or more therapeutic advantages.

[0137] Therefore, in some implementations, the JAK1 pathway inhibitor is a compound or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen atoms in the compound are replaced by deuterium atoms.

[0138] In some embodiments, a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 50 mg to about 600 mg based on free base. Therefore, in some embodiments, a selective JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg based on free base.

[0139] In some implementations, a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 50 mg based on free base.

[0140] In some implementations, a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 100 mg based on free base.

[0141] In some implementations, a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 200 mg based on free base.

[0142] In some implementations, a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 300 mg based on free base.

[0143] In some implementations, a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered at a daily dose of approximately 400 mg based on free base.

[0144] In some implementations, a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 500 mg based on free base.

[0145] In some implementations, a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered at a daily dose of approximately 600 mg based on free base.

[0146] In some implementations, a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered once daily in an amount of about 50 mg based on free base.

[0147] In some implementations, a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered once daily in an amount of about 100 mg based on free base.

[0148] In some implementations, a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered once daily in an amount of about 200 mg based on free base.

[0149] In some implementations, a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered once daily in an amount of about 300 mg based on free base.

[0150] In some implementations, a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered once daily in an amount of about 400 mg based on free base.

[0151] In some implementations, a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered once daily in an amount of about 500 mg based on free base.

[0152] In some implementations, a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered once daily in an amount of about 600 mg based on free base.

[0153] In some embodiments, a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered as one or more extended-release formulations, each of which contains a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0154] This article provides a method for treating obliterative bronchiolitis syndrome in a subject, comprising administering to the subject a daily dose of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof, calculated as about 50 mg to about 600 mg of free base, wherein the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered as one or more extended-release formulations comprising a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0155] This article provides a method for treating obliterative bronchiolitis syndrome in a subject, comprising administering to the subject a daily dose of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof, at a dose of about 100 mg to about 600 mg based on free base, wherein the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered as one or more extended-release formulations comprising a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0156] In some embodiments, a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is administered as one or more extended-release formulations, each of which contains a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0157] Sustained-release formulations of {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azacyclobutane-3-yl}acetonitrile or pharmaceutically acceptable salts thereof (Table 2, Compound 1) are available in U.S. Publication No. 2015-0065484, filed August 6, 2014, which is incorporated herein by reference in its entirety. See also Example B below.

[0158] This article provides a method for treating obliterative bronchiolitis syndrome in subjects, comprising administering to the subject a once-daily dose of {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinyl]piperidin-4-yl}-3[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azacyclobutane-3-yl}acetonitrile or a pharmaceutically acceptable salt thereof, wherein {1-{1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinyl]piperidin-4-yl}-3[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azacyclobutane-3-yl}acetonitrile or a pharmaceutically acceptable salt thereof is administered in one or more sustained-release formulations.

[0159] The embodiments described herein are intended to be combined in any suitable combination as if they were multiple dependent claims (e.g., embodiments relating to selective JAK1 pathway inhibitors and their dosages, embodiments relating to any salt form of the compounds disclosed herein, and embodiments relating to the composition and / or administration can be combined in any combination). For the sake of brevity only, not all possible combinations are listed separately herein.

[0160] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise stated, all stereoisomers, such as enantiomers and diastereomers, are intended. Compounds containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic form. Methods for preparing optically active forms from optically inactive starting materials are known in the art, such as by resolving racemic mixtures or by stereoselective synthesis. Many geometric isomers of alkenes, C=N double bonds, etc., may also be present in the compounds described herein, and all such stable isomers are covered in this invention. The cis and trans geometric isomers of the compounds of this invention are described and can be isolated as mixtures of isomers or as individual isomers.

[0161] In some embodiments, the compound has an (R)-configuration. In some embodiments, the compound has an (S)-configuration.

[0162] Resolution of racemic mixtures of compounds can be achieved by any of a variety of methods known in the art. Example methods include fractional recrystallization using chiral resolving acids, which are optically active salt-forming organic acids. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids such as tartaric acid in D and L forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids, such as β-camphorsulfonic acid. Other resolving agents suitable for fractional recrystallization methods include stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms, or diastereoisomerically pure forms), 2-phenylglycine, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc.

[0163] Resolution of racemic mixtures can also be achieved by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by those skilled in the art.

[0164] The compounds described herein also include tautomeric forms. Tautomeric forms arise from the exchange of single bonds with adjacent double bonds and the accompanying migration of protons. Tautomeric forms include proton tautomers, which are isomeric protonated states having the same empirical formula and total charge. Examples of proton tautomers include keto-enol pairs, amide-imine pairs, lactam-lactam pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions in the heterocyclic system, such as 1H- and 3H-imidazolium, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindole, and 1H- and 2H-pyrazoles. Tautomeric forms can be in equilibrium or spatially locked into one form through appropriate substitution.

[0165] The compounds described herein may also include isotopically labeled compounds of this disclosure. An "isotopic" or "radiolabeled" compound is a compound of this disclosure in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those normally found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated into the compounds of this disclosure include, but are not limited to, those... 2 H (also written as D for deuterium), 3 H (also written as T for tritium), 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 18 F, 35S, 36 Cl、 82 Br、 75 Br、 76 Br、 77 Br、 123 I, 124 I, 125 I and 131 I. For example, one or more hydrogen atoms in the compounds of this disclosure may be replaced by deuterium atoms (e.g., C in formula (I), formula (II) or formula (III)). 1-6 One or more hydrogen atoms of the alkyl group or compounds in Table 2 may optionally be substituted with deuterium atoms, such as -CD3 substituted for -CH3).

[0166] Unless the name indicates a specific stereoisomer, the term "compound" as used herein is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the described structure. Unless otherwise stated, compounds identified herein as a specific tautomer by name or structure are intended to include other tautomers.

[0167] In some embodiments, the compounds described herein or their salts are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially isolated from the environment in which it is formed or detected. Partial isolation may include, for example, compositions rich in the compounds described herein. Substantially isolated may include compositions containing at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compounds described herein or their salts. Methods for separating compounds and their salts are conventional methods in the art.

[0168] All compounds and their pharmaceutically acceptable salts may exist with or be isolated from other substances, such as water and solvents (e.g., hydrates and solvates). When in the solid state, the compounds and their salts described herein may exist in a variety of forms and may be, for example, in the form of solvates (including hydrates). Compounds may be in any solid form, such as polymorphs or solvates; therefore, unless otherwise expressly stated, references to compounds and their salts in this specification should be understood to cover any solid form of the described compounds.

[0169] The phrase “pharmaceutically acceptable” is used herein to refer to those compounds, substances, compositions, and / or dosage forms that are suitable for use in human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within the bounds of reliable medical judgment, and in proportion to a reasonable benefit / risk ratio.

[0170] This invention also includes pharmaceutically acceptable salts of the compounds described herein. The term "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound wherein the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, basic residues such as inorganic or organic acid salts of amines; acidic residues such as alkali metal or organic salts of carboxylic acids; and so on. Pharmaceutically acceptable salts of this invention include, for example, non-toxic salts of parent compounds formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of this invention can be synthesized by conventional chemical methods from parent compounds containing a basic or acidic moiety. Typically, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water, in an organic solvent, or in a mixture of both; typically, non-aqueous media (such as diethyl ether), ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (MeCN) are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, Vol. 10. 17 See also: (Mack Publishing Company, Easton, 1985), p. 1418; Berge et al., J. Pharm.Sci., 1977, 66(1), 1-19; and Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). In some embodiments, the compounds described herein comprise N oxide forms.

[0171] The terms “individual,” “patient,” and “subject” are used interchangeably and refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, suidae, cattle, sheep, horses, or primates, and most preferably humans.

[0172] The phrase “therapeutic effective amount” refers to the amount of an active compound or agent that elicits a biological or medical response in an tissue, system, animal, individual, or human that is sought by researchers, veterinarians, physicians, or other clinicians.

[0173] The term "treating" or "treatment" refers to one or more of the following: (1) suppressing disease; for example, suppressing the disease, symptoms, or symptom of an individual experiencing or exhibiting a pathology or symptom of disease (i.e., preventing further development of the pathology and / or symptom); and (2) improving disease; for example, improving the disease, symptoms, or symptom of an individual experiencing or exhibiting a pathology or symptom (i.e., reversing the pathology and / or symptom), such as reducing the severity of the disease. In one implementation, "treating" or "treatment" includes preventing or reducing the risk of developing disease; for example, preventing or reducing the risk of developing bronchiolitis obliterans syndrome in an individual who may be susceptible to the pathology or symptom of disease (e.g., after a single or double lung transplant) but has not yet experienced or exhibited the disease.

[0174] For the terms “e.g.” and “such as” and their grammatical equivalents, unless otherwise explicitly stated, the phrase “and not limited to” should be understood.

[0175] As used herein, unless the context clearly indicates otherwise, the singular forms “a”, “an”, and “the” include plural indicators.

[0176] As used herein, the term “about” means “approximately” (e.g., approximately 10% of the indicated value plus or minus).

[0177] Combination therapy

[0178] The methods described herein may also include the administration of one or more additional therapeutic agents. These therapeutic agents include anti-inflammatory agents, steroids, immunosuppressants, or therapeutic antibodies.

[0179] Patients diagnosed with post-lung transplant-associated BOS were evaluated to ensure optimal immunosuppression, including adherence to prescription medications and the immunosuppressants used. For patients using cyclosporine, there is evidence indicating that switching from cyclosporine to tacrolimus results in a reduction in predicted FEV1 loss (Sarahrudhi, K. et al., JTCS, April 2004, Vol. 127, No. 4). Once the immunosuppressive regimen is optimized, few treatment options have shown efficacy. Options include:

[0180] ● Azithromycin: In multiple studies, azithromycin has shown improvements in lung function, defined as an increase in FEV1 ≥10, in approximately 35% to 40% of patients. This response appears to be associated with the presence of neutrophils in the BAL fluid (Vos, R. et al. JHLT, 2010, Vol. 29, No. 12). Patients with an FEV1 response to azithromycin have an overall survival advantage compared to those without a response. Furthermore, in post-lung transplant BOS, randomized studies comparing prophylactic azithromycin with placebo resulted in a reduction in BOS cases without affecting overall survival (Vos, R. et al. Eur. Respir. J. 2011, Vol. 37).

[0181] ● Extracorporeal photodissociation (ECP): ECP has shown moderate activity in many single-institution studies, the largest of which enrolled 51 patients. In this study, 61% of patients had long-term stable disease, defined by FEV1 levels maintained at -5 to +5 from pre-ECP baseline for more than 6 months (Benden, EC et al. 2008 Transplantation, Vol. 86, No. 11).

[0182] ● Montelukast: Thirty patients were randomized to receive montelukast or placebo. Montelukast had no effect on the decline in lung function across the entire cohort. However, in a post-hoc subgroup analysis of patients with BOS grade 1, montelukast attenuated further declines in FEV1 in both absolute and predicted FEV1 during the study period (Ruttens, D. et al. Montelukast for bronchiolitis obliterans syndrome after lung transplantation: A randomized controlled trial. PLOS One, April 6, 2018).

[0183] Therefore, in some embodiments, the methods provided herein include administering a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof and cyclosporine or a pharmaceutically acceptable salt thereof.

[0184] In some embodiments, the methods provided herein include administering a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof and azithromycin or a pharmaceutically acceptable salt thereof. In some embodiments, azithromycin is administered at a daily dose of approximately 500 mg for one or two days.

[0185] In some implementations, the methods provided herein include administration of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof and in vitro photodissociation.

[0186] In some embodiments, the methods provided herein include administering a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof and montelukast or a pharmaceutically acceptable salt thereof. In some embodiments, montelukast is administered at a daily dose of about 4 mg to about 10 mg (e.g., about 4 mg, about 5 mg, or about 10 mg daily).

[0187] In some embodiments, the methods provided herein include administering a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof and tacrolimus or a pharmaceutically acceptable salt thereof. In some embodiments, tacrolimus is administered at a daily dose of about 0.075 mg / kg / day to about 0.2 mg / kg / day.

[0188] In some embodiments, the methods provided herein include administering a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof and mycophenolate mofetil or a pharmaceutically acceptable salt thereof. In some embodiments, mycophenolate mofetil or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 500 mg to 1500 mg, for example, about 1440 mg daily.

[0189] In some implementations, the methods provided herein include administration of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof and alemtuzumab. In some implementations, alemtuzumab is administered as a first course of treatment and a second course of treatment twelve months after the first course, wherein the first course of treatment comprises administration of approximately 12 mg / day for five consecutive days and the second course of treatment comprises administration of approximately 12 mg / day for three consecutive days.

[0190] In some embodiments, the methods provided herein include administering a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof and methotrexate or a pharmaceutically acceptable salt thereof. In some embodiments, methotrexate is administered weekly at a dose of about 7.5 mg to about 30 mg (e.g., about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, or about 30 mg).

[0191] In some implementations, the methods provided herein include administration of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof and a corticosteroid or a pharmaceutically acceptable salt thereof.

[0192] In some embodiments, the methods provided herein include administering a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof and everolimus or a pharmaceutically acceptable salt thereof. In some embodiments, everolimus is administered at a daily dose of about 2.5 mg to about 20 mg (e.g., about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, or about 20 mg daily).

[0193] When more than one drug is administered to a subject, it may be administered simultaneously, sequentially, or in combination (e.g., for more than two drugs).

[0194] Composition

[0195] Compounds can be administered in the form of pharmaceutical compositions. These compositions can be prepared in ways well known in the pharmaceutical industry and can be administered via a variety of routes, depending on whether it is for local or systemic treatment and the area to be treated. Administration can be local (including transdermal, epidermal, ocular, and mucous membrane delivery, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or blowing of powders or aerosols, including via nebulizers; intratracheal or intranasal), oral, or parenteral. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion; or intracranial, e.g., intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus dose or, for example, via a continuous infusion pump. Pharmaceutical compositions and formulations for local administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional drug carriers, water, powder or oily bases, thickeners, etc., may be necessary or desired.

[0196] Pharmaceutical compositions may contain a compound as an active ingredient or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the composition is suitable for topical application. In manufacturing the composition, the active ingredient is typically mixed with an excipient, diluted by the excipient, or packaged in this carrier in the form of, for example, capsules, sachets, paper, or other containers. When the excipient is used as a diluent, it can be a solid, semi-solid, or liquid substance, serving as an excipient, carrier, or medium for the active ingredient. Thus, the composition can be a tablet, pill, powder, lozenge, sachet, capsule, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), ointment containing, for example, up to 10% by weight of the active compound, soft gelatin capsules and hard gelatin capsules, suppositories, sterile injections, and sterile packaged powders.

[0197] When preparing a formulation, the active compound can be ground to provide a suitable particle size before being mixed with other ingredients. If the active compound is substantially insoluble, it can be ground to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size can be adjusted by grinding to provide a substantially uniform distribution in the formulation, for example, about 40 mesh.

[0198] The compounds can be ground using known grinding procedures (such as wet milling) to obtain a particle size suitable for tablet formation and other formulation types. Subdivided (nanoparticle) formulations of the compounds of this invention can be prepared by methods known in the art, see, for example, WO2002 / 000196.

[0199] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. Formulations may also include: lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methylparaben and propylparaben; and sweeteners and flavoring agents. The compositions of the present invention can be formulated using methods known in the art to provide a rapid, sustained, or delayed release of the active ingredient upon administration to a patient.

[0200] The components used to formulate the pharmaceutical composition preferably have high purity and are substantially free of potentially harmful contaminants (e.g., at least National Food grade, typically at least analytical grade, and more typically at least pharmaceutical grade). Particularly for human consumption, the composition is preferably manufactured or formulated according to Good Manufacturing Practice (GMP) standards as defined in applicable regulations of the U.S. Food and Drug Administration (FDA). For example, suitable formulations may be sterile and / or substantially isotonic and / or fully compliant with all FDA GMP requirements.

[0201] Active compounds can be effective over a wide dose range and are typically administered at therapeutically effective doses. However, it should be understood that the actual amount of compound administered is usually determined by the physician based on relevant circumstances, including the condition to be treated, the chosen route of administration, the compound actually administered, the individual patient's age, weight and response, and the severity of the patient's symptoms.

[0202] The therapeutic dose of the compounds of the present invention may vary depending on, for example, the specific purpose of treatment, the method of administration of the compound, the patient's health and condition, and the judgment of the prescribing physician. The proportion or concentration of the compounds of the present invention in the pharmaceutical composition may vary depending on many factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration.

[0203] To prepare solid compositions (such as tablets), the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformed composition containing a homogeneous mixture of the compounds of the present invention. When these preformed compositions are referred to as homogeneous, the active ingredient is typically uniformly dispersed throughout the composition, allowing the composition to be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. The solid preformed composition is then subdivided into unit dosage forms of the type described above, containing, for example, from about 0.1 mg to about 1000 mg of the active ingredient of the present invention.

[0204] The tablets or pills of the present invention may be coated or otherwise mixed to provide a dosage form that provides a prolonged effect. For example, the tablets or pills may comprise an internal dose component and an external dose component, the latter being a coating on top of the former. These two components may be separated by an enteric coating layer, which resists disintegration in the stomach and allows the internal component to enter the duodenum intact or delay release. A variety of substances may be used for such enteric coatings or coatings, including various polymeric acids and mixtures of polymeric acids with such substances as shellac, cetyl alcohol, and cellulose acetate.

[0205] Compounds and compositions of the present invention may be incorporated into liquid forms for oral or injectable administration, including aqueous solutions, suitably flavored syrups, water or oil suspensions, and flavored emulsions containing edible oils (such as cottonseed oil, sesame oil, coconut oil, or peanut oil), as well as elixirs and similar pharmaceutical carriers.

[0206] The amount of compound or composition administered to a patient will vary depending on the content, purpose of administration (such as prevention or treatment), patient condition, and method of administration. In therapeutic applications, an amount sufficient to cure or at least partially stop the symptoms of the disease and its complications is administered to a patient already suffering from the disease. The effective dose will depend on the condition of the disease being treated and the judgment of the attending physician, which depends on factors such as disease severity, patient age, weight, and general condition.

[0207] The compositions administered to patients may be in the form of the aforementioned pharmaceutical compositions. These compositions may be sterilized using conventional sterilization techniques or by aseptic filtration. Aqueous solutions may be packaged as is or lyophilized, with the lyophilized formulation mixed with a sterile aqueous carrier prior to administration. The pH of the compound formulation is typically between 3 and 11, more preferably between 5 and 9, and most preferably between 7 and 8. It should be understood that the use of certain of the aforementioned excipients, carriers, or stabilizers may result in the formation of pharmaceutical salts.

[0208] Reagent test kit

[0209] This application also includes useful pharmaceutical kits comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound or any embodiment thereof. Such kits may further include one or more conventional pharmaceutical kit components, such as containers having one or more pharmaceutically acceptable carriers, additional containers, etc., as will be apparent to those skilled in the art. The kit also includes instructions (as an insert or label) indicating the quantity of components to be administered; administration guidelines; and / or guidelines for mixing the components.

[0210] Example

[0211] The invention will be described in more detail through specific embodiments. The following embodiments are provided for illustrative purposes and are not intended to limit the invention in any way. Those skilled in the art will readily recognize that various non-critical parameters can be changed or modified to produce substantially the same results.

[0212] Example A: In vitro JAK kinase assay

[0213] The inhibitory activity of JAK1 pathway inhibitors against JAK targets, which can be used to treat cytokine-related diseases or conditions, was tested using the following in vitro assays described by Park et al., Analytical Biochemistry 1999, 269, 94-104. Catalytic domains of N-terminal His-tagged human JAK1 (aa 837-1142), JAK2 (aa 828-1132), and JAK3 (aa781-1124) were expressed and purified in insect cells using baculoviruses. The catalytic activity of JAK1, JAK2, or JAK3 was determined by measuring the phosphorylation of biotinylated peptides. all uniform hour between point Distinguish fluorescent Light( h omogenous t ime r esolved fPhosphorylation (HTRF) was used to detect phosphorylated peptides. The enzyme, ATP, and 500 nM peptide were measured in 40 μL of a 50 mM Tris (pH 7.8) buffer containing 100 mM NaCl, 5 mM DTT, and 0.1 mg / mL (0.01%) BSA. The IC50 of each compound was measured for each kinase. 50 For 1 mM IC 50 The ATP concentration in the reactants was measured to be 1 mM. The reaction was carried out at room temperature for 1 hour, and then terminated with 20 μL of assay buffer (Perkin Elmer, Boston, MA) containing 45 mM EDTA, 300 nM SA-APC, and 6 nM Eu-Py20. Binding to the europium-labeled antibody was allowed to proceed for 40 minutes, and the HTRF signal was measured on a Fusion plate reader (Perkin Elmer, Boston, MA). The compounds listed in Table 2 were tested in this assay, and the results showed the IC50 values ​​as shown in Table 2. 50 value.

[0214] Example B: Preparation of sustained-release formulation of compound 1

[0215] Sustained-release tablets comprising compound 1 were prepared, wherein the amounts of excipients are shown in the table below. Scheme A was used for SR1 tablets, Scheme B for SR2 tablets, Scheme C for SR3 tablets and 25 mg SR tablets, and Scheme D for SR4 tablets. These procedures are disclosed in U.S. Patent Publication No. 2015 / 0065484, which relates to sustained-release dosage forms of compound 1.

[0216] Option A:

[0217] Step 1. Individually screen compound 1 for adipate, microcrystalline cellulose, hydroxypropyl methylcellulose (Methocel K100LV and Methocel K4M) and lactose monohydrate.

[0218] Step 2. Transfer the screened material from Step 1 to a suitable blender and mix.

[0219] Step 3. Transfer the blend from Step 2 to a suitable granulator and mix.

[0220] Step 4. Add purified water while mixing.

[0221] Step 5. Transfer the particles from Step 4 to a suitable dryer and dry until the LOD is less than 3%.

[0222] Step 6. Screen the particles from step 5.

[0223] Step 7. Mix the screened magnesium stearate with the particles from Step 6 in a suitable blender.

[0224] Step 8. Compress the final blend from step 7 on a suitable rotary tablet press.

[0225] Option B:

[0226] Step 1. Individually screen for adipate, microcrystalline cellulose, hydroxypropyl methylcellulose and pregelatinized starch of Formula I.

[0227] Step 2. Transfer the screened material from Step 1 to a suitable blender and mix.

[0228] Step 3. Transfer the blend from Step 2 to a suitable granulator and mix.

[0229] Step 4. Add purified water while mixing.

[0230] Step 5. Transfer the particles from Step 4 to a suitable dryer and dry until the LOD is less than 3%.

[0231] Step 6. Screen the particles from step 5.

[0232] Step 7. Screen polyoxyethylene, butylated hydroxytoluene and colloidal silica separately.

[0233] Step 8. Transfer the particles from Step 6 and the material from Step 7 to a suitable blender and mix them.

[0234] Step 9. Add the screened magnesium stearate to the substance from Step 8 and continue blending.

[0235] Step 10. Compress the final blend from step 9 on a suitable rotary tablet press.

[0236] Option C:

[0237] Step 1. Individually screen lactose monohydrate, adipate of Formula I compound, microcrystalline cellulose and hydroxypropyl methylcellulose using a suitable filter.

[0238] Step 2. Transfer the screened material from Step 1 to a suitable blender and mix.

[0239] Step 3. Transfer the blend from Step 2 to a suitable granulator and mix.

[0240] Step 4. Add purified water while mixing.

[0241] Step 5. Screen the wet particles using a suitable filter.

[0242] Step 6. Transfer the particles from Step 5 to a suitable dryer and dry until the LOD is less than 3%.

[0243] Step 7. Grind the particles from Step 6.

[0244] Step 8. Mix the screened magnesium stearate with the particles from Step 7 in a suitable blender.

[0245] Step 9. Compress the final blend from Step 8 on a suitable rotary tablet press.

[0246] Option D:

[0247] Step 1. Select pregelatinized starch, adipate of Formula I compound, hydroxypropyl methylcellulose and a portion of the desired microcrystalline cellulose separately using a suitable screener.

[0248] Step 2. Transfer the screened material from Step 1 to a suitable blender and mix.

[0249] Step 3. Transfer the blend from Step 2 to a suitable granulator and mix.

[0250] Step 4. Add purified water while mixing.

[0251] Step 5. Screen the wet particles using a suitable filter.

[0252] Step 6. Transfer the particles from Step 5 to a suitable dryer and dry until the LOD is less than 3%.

[0253] Step 7. Grind the particles from Step 6.

[0254] Step 8. Screen the remaining microcrystalline cellulose and half of the sodium bicarbonate.

[0255] Step 9. Transfer the ground particles from Step 7 and the screened material from Step 8 to a suitable blender and mix them.

[0256] Step 10. Screen the remaining sodium bicarbonate and mix it with the blend from Step 9.

[0257] Step 11. Screen magnesium stearate and mix it with the blend from Step 10.

[0258] Step 12. Compress the final blend from step 11 on a suitable rotary tablet press.

[0259] Composition of SR1: 100 mg sustained-release tablets

[0260]

[0261] aThe conversion factor from adipic acid salt to free base is 0.7911.

[0262] b Add after granulation

[0263] c Removed during processing

[0264] Composition of SR2: 100 mg sustained-release tablets

[0265]

[0266] a The conversion factor from adipic acid salt to free base is 0.7911.

[0267] b Add after granulation

[0268] c Removed during processing

[0269] SR3 (100 mg): Composition of 100 mg extended-release tablets

[0270]

[0271] a The conversion factor from adipic acid salt to free base is 0.7911.

[0272] b Add after granulation

[0273] c Removed during processing

[0274] Composition of SR4: 100 mg extended-release tablets

[0275]

[0276] a The conversion factor from adipic acid salt to free base is 0.7911.

[0277] b Add after granulation

[0278] c Removed during processing

[0279] d Pre-granulation addition and post-granulation addition

[0280] 25 mg SR: Composition of 25 mg extended-release tablets

[0281]

[0282] aThe conversion factor from adipic acid salt to free base is 0.7911.

[0283] b Add after granulation

[0284] c Removed during processing

[0285] Example 1: Safety and efficacy study of compound 1 in participants with post-lung transplant bronchiolitis obliterans syndrome (BOS).

[0286] This phase 1 / 2 study will evaluate the safety and efficacy of compound 1 in participants with post-lung transplant-induced BOS.

[0287] Table 3: Key Research Design Elements

[0288]

[0289] Phase 1 is a dose-selection pilot program that will employ a partially randomized, open-label, parallel cohort design to evaluate safety, tolerability, pharmacokinetic (PK), and disease progression (PD) and determine the recommended Phase 2 dose (RP2D) of compound 1 in participants with post-lung transplant-associated bone disease (BOS). A total of 30 participants with grade 1 or 2 BOS will be assigned to receive one of three compound 1 dose levels (n=10 each); additional details regarding compound 1 dose levels are provided in Table 5. Participants not concurrently taking azoles or low- to moderate CYP3A4-inhibiting azoles (e.g., posacoazole or isovuconazine) at treatment initiation will be randomized to dose level 1 or 2. Participants already taking itraconazole or voriconazole at treatment initiation will receive dose level 3. After Phase 1 is completed, an interim nullipopulation analysis will be performed to determine the overall response rate (ORR) for all participants treated for ≥ 12 weeks. If a response is observed at the dose level selected as RP2D (defined as an increase in FEV1 of ≥10% from baseline, confirmed by two consecutive respiratory measurements at intervals of ≥1 week), the study will proceed to Phase 2. The execution of respiratory measurement assessments is described in the art; see, for example, Miller, MR et al., Eur. Respir. J. 2005; 26: 319-338.

[0290] Phase 2 will employ a single-arm, open-label design to evaluate the efficacy of compound 1 in RP2D and further characterize its safety. Compound 1 treatment will continue until BOS progression (defined as a ≥10% decrease in FEV1 from baseline, confirmed by two consecutive respiratory rate measurements at ≥3-week intervals), unacceptable toxicity, or withdrawal of consent.

[0291] Information regarding the investigational drugs and their administration is provided in Table 4 below.

[0292] Table 4: Study Treatment Information

[0293]

[0294] Table 5: Dosage levels of compound 1

[0295] The dosage levels of compound 1 are presented in Table 5 below:

[0296]

[0297] Participants may have their dosage reduced or modified during treatment based on adverse events (AEs), clinical evaluations, changes in concomitant medications, and laboratory assessments.

[0298] research group

[0299] The inclusion criteria for this study may include:

[0300] ● Male or female, 18 years of age or older

[0301] ● Written informed consent and consent forms (where appropriate) in accordance with institutional standards and all research follow-up and procedures.

[0302] ● Those who have undergone a double lung transplant within 1 to 5 years prior to screening

[0303] ● Baseline FEV1 after lung transplantation, recorded after functional recovery and stabilization (mean of the two highest values ​​measured at least 3 weeks apart according to ISHLT criteria).

[0304] ● Screen for confirmed Grade 1 or 2 BOS cases diagnosed within the past year (according to ISHLT 2002 criteria).

[0305] ● Grade 1 BOS can be defined as a decrease in FEV1 score to 66-80% of the baseline FEV1 after transplantation.

[0306] ● Grade 2 BOS can be defined as a decrease in FEV1 score to 51-65% of the baseline FEV1 after transplantation.

[0307] ● Note: BOS grade can be determined by the average of two measurements taken at least 3 weeks apart, without the patient using an inhaled bronchodilator.

[0308] ● Participants taking azithromycin should have started treatment at least 3 months prior to screening and should take a steady dose (e.g., 250 mg / day, at least 3 times a week).

[0309] ● Note: Participants should have stable or worsening FEV1 after azithromycin administration, as assessed by two respiratory rate measurements at least 3 weeks apart before starting treatment with compound 1.

[0310] ● If participants are currently being treated with corticosteroids, the dosage should be stabilized for 4 weeks prior to screening.

[0311] ● Willing to avoid pregnancy or childbirth according to specified criteria.

[0312] The exclusion criteria for this study may include :

[0313] ● History of single lung transplant, heart-lung transplant, lung retransplant, or any other solid organ transplant.

[0314] ● EBV-negative participants who received EBV donor IgG-positive lungs (at the time of transplantation)

[0315] ● According to the ISHLT 2002 diagnostic criteria, ≥ grade 3 BOS

[0316] ● A decrease in FEV1 can be attributed to one or more causes other than BOS, such as inflammatory complications of lung allogeneic grafts, antibody-mediated rejection, infection, airway dysfunction, allogeneic graft compression, graft expansion damage, vascular obstruction, recurrence of disease in the transplant indication, organizing pneumonia, etc.

[0317] ● Previous systemic treatment for BOS (excluding azithromycin), including in vitro photodissociation, montelukast, and alemtuzumab.

[0318] ● Any changes to the immunosuppressive regimen in the 4 weeks prior to screening.

[0319] ● Untreated and / or symptomatic GERD.

[0320] ● Severe comorbidities, including invasive fungal infections, Bacillus cepacia, non-TB mycobacteria, or TB.

[0321] ● History of diffuse alveolar hemorrhage (DAH)

[0322] ● Currently or previously treated with Janus kinase (JAK) inhibitors.

[0323] ● Participants had laboratory values ​​as defined in Table 6 at the time of screening.

[0324] Table 6: Excluded Laboratory Values

[0325]

[0326] ● Active HBV or HCV infection requiring treatment, or at risk of HBV reactivation (i.e., HBsAg positive). Participants who are HBsAg negative and total HBc antibody positive may be included if HBV DNA is undetectable at screening. Participants who are HCV antibody positive are eligible only if their PCR is negative for HCV RNA. Participants with unknown or indeterminate immune status can obtain confirmatory immune status results prior to participation. Previous serological results are acceptable for eligibility determination.

[0327] ● Known HIV infection.

[0328] ● Screening is conducted for individuals with a history of active malignant tumors within the past 3 years, excluding superficial basal cell carcinoma and squamous cell carcinoma of the skin, as well as cervical carcinoma in situ that has undergone adequate treatment.

[0329] ● Pregnant or breastfeeding women.

[0330] ● Expected demand for live vaccines (including attenuated vaccines) during the first year of the study.

[0331] ● Treatment with the investigational drug, procedure, or device within 30 days of randomization or within 5 half-lives of the investigational product (whichever is longer).

[0332] ● Known allergy, hypersensitivity or intolerance to any investigational drug, excipient or similar compound.

[0333] ● Researchers believe that participants are unable or unlikely to adhere to the dosage schedule and study evaluation.

[0334] ● In the researcher's judgment, any situation that would interfere with full participation in the study, including administration of study drugs / treatments and participation in study follow-ups required for participation; poses a significant risk to participants; or interferes with the interpretation of study data.

[0335] ● The participant (or their legally authorized representative) does not understand the ICF (Informed Consent Form) or is unwilling to sign the ICF.

[0336] Based on the foregoing description, various modifications to the invention other than those described herein will be apparent to those skilled in the art. Such modifications are also intended to fall within the scope of the appended claims. Every reference cited in this application (including all patents, patent applications, and publications) is incorporated herein by reference in its entirety.

[0337] This disclosure relates to the following implementation plan.

[0338] 1. A method for treating chronic lung allogeneic graft dysfunction in a subject, the method comprising administering a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof to the subject.

[0339] 2. The method as described in Implementation Scheme 1, wherein the chronic lung allogeneic graft dysfunction is bronchiolitis obliterans syndrome.

[0340] 3. The method as described in implementation scheme 1 or 2, wherein the subject is a lung transplant recipient.

[0341] 4. The method as described in implementation scheme 1 or 2, wherein the subject is a double lung transplant recipient.

[0342] 5. The method as described in Implementation Scheme 2, wherein the subject suffers from obliterative bronchiolitis syndrome of grade 0p, 1, 2 or 3 as determined by the International Society for Heart and Lung Transplantation (ISHLT) criteria.

[0343] 6. The method as described in embodiment 2, wherein treatment of bronchiolitis obliterans syndrome comprises an increase of approximately 10% or more in FEV1 twelve weeks after the first administration of the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0344] 7. The method of any one of embodiments 1-6, wherein the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is a JAK1 / 2 inhibitor or a pharmaceutically acceptable salt thereof.

[0345] 8. The method of embodiment 7, wherein the JAK1 / 2 inhibitor is ruxolitinib or a pharmaceutically acceptable salt thereof, or baricitinib or a pharmaceutically acceptable salt thereof.

[0346] 9. The method of any one of embodiments 1-6, wherein the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof has higher selectivity for JAK1 than for JAK2, JAK3 and Tyk2.

[0347] 10. The method of embodiment 9, wherein the JAK1 pathway inhibitor is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azacyclobutane-3-yl}acetonitrile, or a pharmaceutically acceptable salt thereof.

[0348] 11. The method of embodiment 9, wherein the JAK1 pathway inhibitor is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azacyclobutane-3-yl}acetonitrile adipate.

[0349] 12. A method for reducing the risk of bronchiolitis obliterans syndrome in a subject, the method comprising administering a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof to the subject.

[0350] 13. The method as described in embodiment 12, wherein the subject is a lung transplant recipient.

[0351] 14. The method as described in embodiment 12, wherein the subject is a double lung transplant recipient.

[0352] 15. The method of any one of embodiments 12-14, wherein the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is a JAK1 / 2 inhibitor or a pharmaceutically acceptable salt thereof.

[0353] 16. The method of embodiment 15, wherein the JAK1 / 2 inhibitor is ruxolitinib or a pharmaceutically acceptable salt thereof, or baricitinib or a pharmaceutically acceptable salt thereof.

[0354] 17. The method of any one of embodiments 12-14, wherein the JAK1 pathway inhibitor is more selective for JAK1 than for JAK2, JAK3 and Tyk2.

[0355] 18. The method of embodiment 17, wherein the JAK1 pathway inhibitor is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azacyclobutane-3-yl}acetonitrile, or a pharmaceutically acceptable salt thereof.

[0356] 19. The method of embodiment 17, wherein the JAK1 pathway inhibitor is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azacyclobutane-3-yl}acetonitrile adipate.

[0357] 20. A method for reducing the risk of lung retransplantation in a subject, the method comprising administering to the subject a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0358] 21. A method for reducing the risk of hospitalization in a subject, the method comprising administering to the subject an effective amount of a JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof, wherein the subject: (a) has been diagnosed with bronchiolitis obliterans syndrome; (b) has undergone a lung transplant within 1 to 5 years prior to administration of the JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof; and (c) does not have a decrease in FEV1 due to causes other than bronchiolitis obliterans syndrome.

Claims

1. Use of a selective JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating chronic lung allogeneic graft dysfunction in a subject, wherein said selective JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bispyrazol-1-yl)azacyclobutan-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide or a pharmaceutically acceptable salt thereof.

2. The use according to claim 1, wherein the chronic lung allogeneic graft dysfunction is bronchiolitis obliterans syndrome.

3. The use according to claim 1 or 2, wherein the subject is a lung transplant recipient.

4. The use according to claim 1 or 2, wherein the subject is a double lung transplant recipient.

5. The use according to claim 2, wherein the subject suffers from obliterative bronchiolitis syndrome of grade 0p, 1, 2 or 3 as determined by the International Society for Heart and Lung Transplantation (ISHLT) criteria.

6. The use according to claim 2, wherein the subject's FEV1 increases by about 10% or more twelve weeks after the first administration of the selective JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof.

7. The use according to claim 1, wherein the selective JAK1 pathway inhibitor is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bispyrazol-1-yl)azacyclobutan-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide phosphate.

8. Use in the preparation of a medicament for reducing the risk of bronchiolitis obliterans syndrome in a subject, wherein said selective JAK1 pathway inhibitor or pharmaceutically acceptable salt thereof is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bispyrazol-1-yl)azacyclobutane-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide or a pharmaceutically acceptable salt thereof.

9. The use according to claim 8, wherein the subject is a lung transplant recipient.

10. The use according to claim 8, wherein the subject is a double lung transplant recipient.

11. The use according to claim 8, wherein the selective JAK1 pathway inhibitor is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bispyrazol-1-yl)azacyclobutan-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide phosphate.

12. Use of a selective JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for reducing the risk of lung retransplantation in a subject, wherein said selective JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bispyrazol-1-yl)azacyclobutane-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide or a pharmaceutically acceptable salt thereof.

13. Use of a selective JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for reducing the risk of hospitalization in a subject, wherein the subject: (a) has been diagnosed with bronchiolitis obliterans syndrome; (b) has undergone a lung transplant within 1 to 5 years prior to administration of the selective JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof; and (c) does not have a decrease in FEV1 due to causes other than bronchiolitis obliterans syndrome, wherein the selective JAK1 pathway inhibitor or a pharmaceutically acceptable salt thereof is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bispyrazol-1-yl)azacyclobutane-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide or a pharmaceutically acceptable salt thereof. 14.4 Use of [3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bispyrazol-1-yl)azacyclobutane-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of a subject with bronchiolitis obliterans syndrome.

15. The use according to claim 14, wherein the pharmaceutically acceptable salt is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bispyrazol-1-yl)azacyclobutane-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide phosphate.

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